Toxoplasmosis refers to a disease caused by the parasite Toxoplasma gondii (T. gondii). The active infection destroys tissues, especially brain and eye in the fetus, newborn infant, immune compromised persons and those with retinal disease. In the presence of a normal immune response, the parasite remains as a chronic cryptic, latent brain infection, that can recrudesce and thus cause eye damage throughout the life of the host. About four thousand cases of newly active retinal disease are diagnosed in the U.S. each year. Importantly, this parasite chronically infects 30-50% of human population worldwide, with unknown consequences of this chronic infection of the brain in 2-3 billion persons throughout the world. Herein we describe various embodiments of an immunosense vaccine consisting of peptides created from immunogenic parasite proteins.
Human cells have a major histocompatibility complex (MHC) Class I processing pathway in which the proteasome in the cytosol degrades proteins from T. gondii into chains of eight to ten amino acids. These peptides associated with MHC Class I molecules then travel through the endoplasmic reticulum, and are presented at the surface of all cells so that the T cell receptors of cytotoxic T cells (CTLs) and IFN-γ producing CD8+ T cells can recognize the MHC molecule and bound peptide. Thus, IFN-γ producing CD8+ T cells are able to identify the peptides as self or non-self. Cells that present non-self peptides are killed and/or elicit IFN-γ. In this manner, CD8+ T lymphocytes play a major role in protection against T. gondii by secreting IFN-γ which activates macrophages to inhibit replication, kill the parasite, and induce lysis of infected cells. Thus, this obligate intracellular parasite loses its intracellular niche.
Since CD8+ T cells recognize target cells by peptide epitopes presented in the context of MHC Class I molecules, it is of great interest to identify MHC Class I restricted peptide epitopes from specific T. gondii antigens to facilitate creating vaccines that stimulate cell-mediated immune responses. The identification of CD8+ T cell responses provides peptide antigens that can be used for directly monitoring CD8+ T cell responses resulting from vaccination.
Toxoplasma gondii is an intracellular parasite which infects a broad range of mammalian hosts and can cause severe disease in immune-compromised or immunologically immature persons. The infection can cause severe ocular, neurologic, and systemic disease in these settings. Because no medicines eradicate all life cycle stages of this parasite, development of a vaccine against T. gondii is extremely useful, especially a vaccine that can prevent acquisition of parasite completely.
A preferred vaccine to protect against toxoplasmosis in humans includes epitopes that elicit a protective Th1 biased-immune response, characterized by the generation of long-lived IFN-γ-producing CD8+ T cells. CD4+ and CD8+ T cells have a critical role in protective immunity to T. gondii in murine models and humans. CD8+ T cells and interferon gamma (IFN-γ) are significant effectors mediating resistance to acute and chronic T. gondii infection. Peptide-based vaccines derived from CD8+ T cell epitopes are a promising strategy to mobilize the immune system against T. gondii in humans. However, until now no T. gondii specific HLA restricted CD8+ T cell epitopes that were proven to be protective had been identified.